PURPOSE: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). EXPERIMENTAL DESIGN: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. RESULTS: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. CONCLUSIONS: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.
PURPOSE:Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). EXPERIMENTAL DESIGN:IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. RESULTS: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. CONCLUSIONS: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: W A May; M L Gishizky; S L Lessnick; L B Lunsford; B C Lewis; O Delattre; J Zucman; G Thomas; C T Denny Journal: Proc Natl Acad Sci U S A Date: 1993-06-15 Impact factor: 11.205
Authors: Heikki Joensuu; Mikael Eriksson; Kirsten Sundby Hall; Jörg T Hartmann; Daniel Pink; Jochen Schütte; Giuliano Ramadori; Peter Hohenberger; Justus Duyster; Salah-Eddin Al-Batran; Marcus Schlemmer; Sebastian Bauer; Eva Wardelmann; Maarit Sarlomo-Rikala; Bengt Nilsson; Harri Sihto; Odd R Monge; Petri Bono; Raija Kallio; Aki Vehtari; Mika Leinonen; Thor Alvegård; Peter Reichardt Journal: JAMA Date: 2012-03-28 Impact factor: 56.272
Authors: Philippe Meyer; Chrisostomos Prodromou; Bin Hu; Cara Vaughan; S Mark Roe; Barry Panaretou; Peter W Piper; Laurence H Pearl Journal: Mol Cell Date: 2003-03 Impact factor: 17.970
Authors: S Hirota; K Isozaki; Y Moriyama; K Hashimoto; T Nishida; S Ishiguro; K Kawano; M Hanada; A Kurata; M Takeda; G Muhammad Tunio; Y Matsuzawa; Y Kanakura; Y Shinomura; Y Kitamura Journal: Science Date: 1998-01-23 Impact factor: 47.728
Authors: Jefferson Terry; Joanna M Lubieniecka; Wanda Kwan; Suzanne Liu; Torsten O Nielsen Journal: Clin Cancer Res Date: 2005-08-01 Impact factor: 12.531
Authors: Adeela Kamal; Lia Thao; John Sensintaffar; Lin Zhang; Marcus F Boehm; Lawrence C Fritz; Francis J Burrows Journal: Nature Date: 2003-09-25 Impact factor: 49.962
Authors: George D Demetri; Margaret von Mehren; Charles D Blanke; Annick D Van den Abbeele; Burton Eisenberg; Peter J Roberts; Michael C Heinrich; David A Tuveson; Samuel Singer; Milos Janicek; Jonathan A Fletcher; Stuart G Silverman; Sandra L Silberman; Renaud Capdeville; Beate Kiese; Bin Peng; Sasa Dimitrijevic; Brian J Druker; Christopher Corless; Christopher D M Fletcher; Heikki Joensuu Journal: N Engl J Med Date: 2002-08-15 Impact factor: 91.245
Authors: P W Manley; S W Cowan-Jacob; E Buchdunger; D Fabbro; G Fendrich; P Furet; T Meyer; J Zimmermann Journal: Eur J Cancer Date: 2002-09 Impact factor: 9.162
Authors: Michael C Heinrich; Christopher L Corless; George D Demetri; Charles D Blanke; Margaret von Mehren; Heikki Joensuu; Laura S McGreevey; Chang-Jie Chen; Annick D Van den Abbeele; Brian J Druker; Beate Kiese; Burton Eisenberg; Peter J Roberts; Samuel Singer; Christopher D M Fletcher; Sandra Silberman; Sasa Dimitrijevic; Jonathan A Fletcher Journal: J Clin Oncol Date: 2003-12-01 Impact factor: 44.544
Authors: Xiachang Wang; Yinan Zhang; Larissa V Ponomareva; Qingchao Qiu; Ryan Woodcock; Sherif I Elshahawi; Xiabin Chen; Ziyuan Zhou; Bruce E Hatcher; James C Hower; Chang-Guo Zhan; Sean Parkin; Madan K Kharel; S Randal Voss; Khaled A Shaaban; Jon S Thorson Journal: Angew Chem Int Ed Engl Date: 2017-01-31 Impact factor: 15.336